Arachidonic acid is known to be the biological precursor of several groups of endogenous metabolites, prostaglandins including prostacyclins, thromboxanes and leukotrienes. The first step of arachidonic acid metabolism is the release of arachidonic acid and related unsaturated fatty acids from membrane phospholipids via the action of phospholipase. Free fatty acids are then metabolized either by cyclooxygenase to produce the prostaglandins and thromboxanes or by lipoxygenase to generate hydroperoxy fatty acids which may be further converted to the leukotrienes. Leukotrienes have been implicated in the pathophysiology of inflammatory diseases including rheumatoid arthritis, gout, asthma, ischemia reperfusion injury, psoriasis and inflammatory bowel disease. Compounds that inhibit lipoxygenase are expected to provide significant new therapy for both acute and chronic inflammatory conditions.
Recently, several review articles on lipoxygenase inhibitors have been reported. See H. Masamune and L. S. Melvin, Sr., in: Annual Reports in Medicinal Chemistry 24 (1989) pp. 71-80 (Academic); and B. J. Fitzsimmons and J. Rokach in: Leukotrienes and Lipoxygenases (1989) pp. 427-502 (Elsevier).
Offenlegungsschrift 1695595 discloses certain pyrimido-benzothiazines which are useful for blocking phosphodiesterases. Sakamuki, M. et al. and Sako, M. et al. both in 12th Symposium on Progress in Organic Reactions and Syntheses, Symposium Papers, Nov. 8-9, 1985, Nagoya, pp. 186-189 and p. 190; and Sako, M. et al., Chem. Pharm. Bull., 32, pp. 2474-2476 (1984), disclose the syntheses of certain pyrimido-benzothiazines.
Certain derivatives of phenothiazine of the general formula ##STR2## wherein X is, inter alia, S, SO or SO.sub.2 ; R.sup.1 is, inter alia, H or (C.sub.1 -C.sub.6)alkyl; R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are inter alia, independently H, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl or --(CH.sub.2).sub.n M where n is 0-6 and M is halogen or various groups and T is H or OR.sup.15 where R.sup.15 is H or various groups are disclosed in EP 138481, published Apr. 24, 1985 and corresponding to JP 60155165, as leukotriene biosynthesis inhibitors useful in treating allergic conditions, asthma, cardiovascular disorders, inflammation and certain skin diseases.